Oxidative alkylation of cyclic benzyl ethers with malonates and ketones using oxygen as the terminal oxidant

Article abstract of DOI:10.1055/s-0028-1087376

A simple oxidative alkylation of cyclic benzyl ethers with malonates and ketones was developed using a mixture of Cu(OTf)₂, InCl₃, and NHPI as catalyst under an atmospheric pressure of oxygen. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087376

1
38
CLUSTER
Oxidative Alkylation of Cyclic Benzyl Ethers with Malonates and Ketones
Using Oxygen as the Terminal Oxidant
yl Ethers -Jin Yoo, Camille A. Correia, Yuhua Zhang, Chao-Jun Li*a
a
a
b,1
O
W
xidative Alkylation of
o
Cyclic
B
enz
o
a
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax +1(514)3983797; E-mail: cj.li@mcgill.ca
Department of Chemistry, Tulane University, New Orleans, LA, 70118, USA
b
Received 23 September 2008
and cost. With this in mind, we and Murahashi have re-
cently disclosed improved protocols of oxidative coupling
reactions between C–H bonds adjacent to nitrogen and
various nucleophiles utilizing oxygen under atmospheric
pressure as the terminal oxidant (Scheme 1).6
Abstract: A simple oxidative alkylation of cyclic benzyl ethers
with malonates and ketones was developed using a mixture of
Cu(OTf) , InCl , and NHPI as catalyst under an atmospheric pres-
2
3
sure of oxygen.
Key words: copper, indium, oxygen, cross-coupling, radical reac-
tions
As part of our continuing interest in developing oxidative
C–C coupling reaction using oxygen as the terminal oxi-
dant, we wish to report a simple and effective oxidative
The development of efficient methods towards carbon– alkylation of cyclic benzyl ethers with malonates and ke-
carbon (C–C) bond-formation processes is of great inter- tones catalyzed by a mixture of Cu(OTf) , InCl , and
2
3
est to chemists. One of the most important set of reactions NHPI under an atmospheric pressure of oxygen.
for the formation of C–C bonds is the metal-catalyzed
cross-coupling reactions. However, a drawback to this
We began the optimization process by examining the orig-
inal copper- and indium-catalyzed oxidative coupling re-
action between malonates and benzyl ethers mediated by
DDQ. Initially, we attempted the oxidative coupling reac-
2
strategy is the use of prefunctionalized starting materials
that places additional synthetic steps towards the overall
synthesis of a single C–C bond. Thus, a great deal of in-
terest has been generated for the direct use of carbon–hy-
drogen (C–H) bonds as coupling partners for C–C bond
Table 1 Optimization of the Oxidative Alkylation Reaction of Iso-
chroman with Dimethyl Malonatea
3
formation.
Cu(OTf)2 (cat.), InCl3 (cat.)
O
O
O
O
Recently, we and others have demonstrated the use of rad-
ical initiators as powerful mediators for the oxidative cou-
pling between various nucleophiles with allylic, benzylic,
and propargylic C–H bonds. Oxidants most commonly
NHPI (cat.)
+
OMe
O
MeO
OMe
MeO
O2 (1 atm), temp
O
1
a
2a
3
a
4
utilized for these reactions are organic peroxides and
5
benzoquinones. While these reagents are quite powerful Entry
and efficient, they do not represent the most ideal oxidant.
Cu(OTf)
InCl
NHPI
(mol%)
Temp
Yield
(%)
2
3
(
mol%)
(mol%)
5.0
5.0
5.0
5.0
5.0
–
(°C)
r.t.
r.t.
55
55
75
55
55
55
55
55
55
Oxygen is a highly desirable oxidant due to its availability
1b,c
5.0
20
20
20
20
20
20
20
20
10
40
20
0
0
2c
3c
4
5.0
R4
R2
N
R4
5.0
41
77
57
31
20
72
64
76
17
H
NO2
R2
R1
NO2
CuBr (cat.)
O2 (1 atm)
R3
5.0
N
H
COOR5
R1
R2
N
COOR5
COOR5
5
5.0
R3
2
H O
COOR5
H
R1
6
10
–
CuBr (cat.)
R3
®
T-HYDRO (cat.)
DME
ArB(OH)2
R2
7
10
O2 (1 atm)
8
2.5
2.5
5.0
5.0
5.0
N
Ar
9
5.0
5.0
5.0
R1
R3
10
Scheme 1 Copper-catalyzed oxidative coupling reactions of C–H
bonds adjacent to nitrogen using air as the terminal oxidant
1d
1
a
b
c
d
Dimethyl malonate (0.5 mmol), isochroman (2.5 mmol).
Dimethyl malonate (0.6 mmol), isochroman (0.5 mmol).
CH Cl (c 0.25 M).
SYNLETT 2009, No. 1, pp 0138–0142
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087376; Art ID: S08908ST
2
2
Air instead of oxygen.
©
Georg Thieme Verlag Stuttgart · New York

CLUSTER
Oxidative Alkylation of Cyclic Benzyl Ethers
139
tion by simply replacing the DDQ with a balloon of oxy- idative coupling reaction. On the other hand, only cyclic
gen. However, we did not observe the desired product. benzyl ethers were good substrates. The use of noncyclic
Through examination of the literature, we discovered that benzyl ethers, such as benzyl methyl ether, provided the
NHPI (N-hydroxyphthalimide) is a well-known additive desired product in small amounts that could not be sepa-
that activates benzylic C–H bonds towards oxidation in rated from undesired side products. We also attempted to
the presence of oxygen gas.7,8
utilize other types of nucleophiles such as 2,4-pentanedi-
one, but observed a complex mixture along with the de-
sired product. However, we were able to oxidatively
couple simple ketones using the optimized conditions
with a slight increase in temperature (Scheme 3).11
Our initial attempt at utilizing the NHPI as an additive did
not provide the desired product (Table 1, entry 1) and only
the oxidation product of the isochroman was observed.
Increasing the amount of isochroman available to the re-
action did not produce any positive results (entry 2). How-
ever, by increasing the temperature, the desired oxidative
coupling product 3 was obtained with moderate yields
Several simple ketones bearing enolizable C–H bonds
were found to be amenable to the copper- and indium-cat-
alyzed oxidative coupling reaction. In general, ketones
bearing aromatic rings were found to be excellent sub-
strates. However, ketones bearing only aliphatic chains
were found to be poor substrates.
(
entry 3). The yield of 3 was improved when the reaction
was performed under solvent-free conditions (entry 4).
Selective removal of each of the catalyst components
showed that both the copper and indium salts were neces- Although the exact role of the metal catalysts in the oxi-
sary for the successful oxidative coupling between di- dative alkylation reaction is unknown, we hypothesized
methyl malonate and isochroman (entries 6 and 7).9 that benzylic alcohol 6 could be a potential intermedi-
Increasing the amount of NHPI in the system did not im- ate.1 Thus, we independently synthesized 6 through a
prove the reaction (entry 10), while replacing oxygen with two-step procedure that involved a DDQ-mediated oxida-
2,13
air decreased the yield of the reaction (entry 11).
tive dimerization of isochroman and an acid-catalyzed
cleavage reaction.14 Next, when benzyl alcohol 6 was
used as a substrate instead of the isochroman, the alkyla-
tion product was observed, albeit at a slightly lower yield
With the optimized reaction conditions in hand, we exam-
ined the scope of the oxidative alkylation of malonates to
1
0
cyclic benzyl ethers (Scheme 2). In most cases, a variety
of malonates were found to be good substrates for the ox-
(
Scheme 4).
R3
R3
O
O
n
n
Cu(OTf)2 (5.0 mol%), InCl3 (5.0 mol%)
NHPI (20 mol%)
1
OR1
O
R2
R O
O
+
R2
OR1
O2 (1 atm), 55 °C
1
1
a–f
2a–c
R O
O
(
0.5 mmol)
(2.5 mmol)
O
3
a–h
1
R
R
R
= Me, Et, i-Pr, Bn
= H, Me, Cl
= H, Me
2
3
n = 1, 2
O
O
O
O
O
O
iPrO
OPr
i
BnO
OBn
MeO
OMe
EtO
OEt
O
O
O
O
O
O
3
a
3b
(83%)
3c
(68%)
3d
(
77%)
(77%)
O
O
O
O
OMe
Me
Cl
MeO
OMe
MeO
OMe
MeO
OMe
MeO
O
O
O
O
O
O
O
O
1
:1
3
e
3f
(60%)
3g
3h
(
42%)
(61%)
(41%)
Scheme 2 Scope of the oxidative alkylation of malonates with cyclic benzyl ethers
Synlett 2009, No. 1, 138–142 © Thieme Stuttgart · New York

1
40
W.-J. Yoo et al.
CLUSTER
O
Cu(OTf)2 (5.0 mol%), InCl3 (5.0 mol%)
NHPI (20 mol%)
R2
O
O
R1
O
+
R1
O2 (1 atm), 75 °C
R2
(
0.5 mmol)
a–h
(2.5 mmol)
4
2a
5
a–h
1
2
R
R
= alkyl, aryl
= H, alkyl
O
O
O
O
O
Br
O
O
O
Br
5
a
5b
5c
5d
(58%)
(
75%)
(75%)
(82%)
O
O
O
O
O
O
O
O
O
(
1:2.3)
(1:1.4)
5e
5f
5g
5h
(
65%)
(69%)
(19%)
(1%)
Scheme 3 Scope of the oxidative alkylation of simple ketones with isochroman
Cu(OTf)2 (cat.), InCl3 (cat.)
NHPI (cat.)
O
O
O
O
+
O
MeO
OMe
55 °C
MeO
OMe
(60%)
OH
O
1a
6
3a
Scheme 4 Alkylation of benzyl alcohol 6 with dimethyl malonate
With this information, a likely reaction pathway for the In summary, we have demonstrated that an oxidative
oxidative alkylation of malonates with cyclic benzyl alkylation of cyclic benzyl ethers with malonates or ke-
ethers is proposed (Scheme 5).
tones is possible using a mixture of indium and copper
salts as catalyst. Furthermore, through the addition of
NHPI as a co-catalyst, oxygen under atmospheric pressure
was utilized as the terminal oxidant. In addition, we have
established that the key intermediate for this oxidative
coupling reaction is the benzylic alcohol. Further investi-
gations into the potential use of NHIP as a catalyst for ox-
idative coupling reactions using oxygen as the terminal
oxidant is currently under investigation and will be dis-
closed in due course.
The reaction can be envisioned to proceed through the ini-
tial radical-induced H-abstraction of cyclic benzyl ether
2
a to generate the benzyl radical 7. The key radical spe-
cies responsible for the H-abstraction, phthalimide N-oxyl
PINO), was generated through the interaction between
(
NHPI and dioxygen. Next, benzyl radical 7 can be trapped
with dioxygen and in the presence of H donors (2a, NHPI,
etc.) produces hydroperoxide 8. Metal-induced decompo-
sition of 8 would then form the key alcohol intermediate
15
6
, which can follow two possible reaction pathways. The
undesired pathway is the overoxidation of alcohol 6 to its
corresponding lactone 9. Alternatively, 9 can be generated
directly from 8 by loosing water. The other potential re-
action pathway can be realized through the copper- and
indium-catalyzed alkylation of malonate 1a to provide the
desired oxidative coupling product 3a.
Acknowledgment
1
6
This work was supported by the Canada Research Chair (Tier I)
foundation (to C.-J.L.), NSERC, and the US NSF-EPA joint pro-
gram for a Sustainable Environment. W.-J.Y. and C.A.C. would
like to thank NSERC and McGill University, (Bill and Christina
Chan Fellowship) respectively, for post-graduate fellowships. We
Synlett 2009, No. 1, 138–142 © Thieme Stuttgart · New York

CLUSTER
Oxidative Alkylation of Cyclic Benzyl Ethers
141
O2
O
O
N
O
N
OH
O
O
PINO
NHPI
O
O
2a
7
O2, H-donor
[
Cu]/[In]
[Cu]/[In]
O
O
O
O
O
O
MeO
OMe
O
OH
MeO
OMe
OH
O
6
8
1a
3a
[O]
–
H2O
O
O
9
Scheme 5 Proposed reaction pathway for the oxidative alkylation of isochroman with dimethyl malonate
would also like to thank Mr. René-Viet Nguyen for the synthesis of
some starting materials.
D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
8928. (i) Zhang, Y.; Li, C.-J. Eur. J. Org. Chem. 2007,
4654. (j) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem. Int. Ed.
2
007, 46, 6505. (k) Deng, G.; Zhao, L.; Li, C.-J. Angew.
References and Notes
Chem. Int. Ed. 2008, 47, 6278. (l) Zhao, L.; Li, C.-J. Angew.
Chem. Int. Ed. 2008, 47, 7075. (m) Li, Z.; Yu, R.; Li, H.
Angew. Chem. Int. Ed. 2008, 47, 7497. (n) Borduas, N.;
Powell, D. A. J. Org. Chem. 2008, 73, 7822.
(
(
(
1) New address: Y. Zhang, Department of Chemistry,
Washington University, Campus Box 1134, One Brookings
Drive, St. Louis, Missouri 63130, USA.
2) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
(
5) For examples of oxidative C–C bond-formation reactions
using DDQ as the terminal oxidant, see: (a) Zhang, Y.; Li,
C.-J. J. Am. Chem. Soc. 2006, 128, 4242. (b) Zhang, Y.; Li,
C.-J. Angew. Chem. Int. Ed. 2006, 45, 1949. (c) Cheng, D.;
Bao, W. Adv. Synth. Catal. 2008, 350, 1263. (d) Cheng, D.;
Bao, W. J. Org. Chem. 2008, 73, 6881.
6) (a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am.
Chem. Soc. 2003, 125, 15312. (b) Baslé, O.; Li, C.-J. Green
Chem. 2007, 9, 1047. (c) Murahashi, S.-I.; Nakae, T.; Terai,
H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005.
2004.
3) For recent reviews, see: (a) Jia, C.; Kitamura, T.; Fujiwara,
Y. Acc. Chem. Res. 2001, 34, 633. (b) Ritleng, V.; Sirlin,
C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. (c) Godula, K.;
Sames, D. Science 2006, 312, 67. (d) Yu, J.-Q.; Giri, R.;
Chen, X. Org. Biomol. Chem. 2006, 4, 4041. (e) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(
(
(
(
f) Herrerias, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev.
(
d) Baslé, O.; Li, C.-J. Org. Lett. 2008, 10, 3661.
2007, 107, 2546. (g) Li, C.-J. Acc. Chem. Res. 2008, in
7) For reviews on the use of NHPI as an effective catalyst for
oxidation of C–H bonds in oxygen, see: (a) Ishii, Y.;
Sakaguchi, S.; Iwahama, T. Adv. Synth. Catal. 2001, 343,
press.
(
4) For examples of oxidative C–C bond-formation reactions
using peroxides as the terminal oxidant, see: (a) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (b) Li, Z.; Li,
C.-J. Org. Lett. 2004, 6, 4997. (c) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 3672. (d) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 6968. (e) Li, Z.; Li, C.-J. Eur. J. Org.
Chem. 2005, 3173. (f) Murahashi, S.-I.; Komiya, N.; Terai,
H. Angew. Chem. Int. Ed. 2005, 44, 6931. (g) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2006, 128, 56. (h) Li, Z.; Bohle,
393. (b) Galli, C.; Gentili, P.; Lanzalunga, O. Angew. Chem.
Int. Ed. 2008, 47, 4790.
8) For representative examples of NHPI as an effective catalyst
for oxidation of C–H bonds in oxygen, see: (a) Ishii, Y.;
Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama, T.;
Nishiyama, Y. J. Org. Chem. 1995, 60, 3934. (b) Ishii, Y.;
Iwahama, T.; Sakaguchi, S.; Nakayama, K.; Nishiyama, Y.
J. Org. Chem. 1996, 61, 4520. (c) Kato, S.; Iwahama, T.;
Synlett 2009, No. 1, 138–142 © Thieme Stuttgart · New York

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W.-J. Yoo et al.
CLUSTER
Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1998, 63, 222.
(4a) (0.058 mL, 0.500 mmol) and isochroman (2a) (0.31
mL, 2.5 mmol). The test tube was placed in an oil bath set at
75 °C and was allowed to stir overnight. The reaction
mixture was allowed to cooled to r.t., and the crude reaction
mixture was purified by silica gel column chromatography
(EtOAc–hexane, 1:5) to provide the desired alkylation
(
d) Sakaguchi, S.; Nishiwaki, Y.; Kitamura, T.; Ishii, Y.
Angew. Chem. Int. Ed. 2001, 40, 222. (e) Hara, T.;
Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2001,
6
6, 6425. (f) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y.
Angew. Chem. Int. Ed. 2004, 43, 1120.
9) Lewis acids such as Bi(OTf) , Yb(OTf) , FeCl , Co(OAc)
2
(
product 5a (95.0 mg, 0.379 mmol, 75%) as a pale yellow oil.
3
3
3
1
were screened as co-catalysts with Cu(OTf) . In all cases,
H NMR (400 MHz, CDCl ): d = 8.03–8.00 (m, 2 H), 7.59–
2
3
the yields were considerably lower (<40%) compared to
InCl3.
7.55 (m, 1 H), 7.49–7.45 (m, 2 H), 7.22–7.18 (m, 2 H), 7.16–
7.10 (m, 2 H), 5.51 (dd, J = 8.4, 3.2 Hz, 1 H), 4.12 (ddd,
J = 10.8, 5.6, 3.6 Hz, 1 H), 3.82 (ddd, J = 3.6, 9.6, 11.2 Hz,
1 H), 3.63 (dd, J = 8.8, 16.6 Hz, 1 H), 3.33 (dd, J = 3.6, 16.0
Hz, 1 H), 3.03 (ddd, J = 5.6, 9.6, 15.6 Hz, 1 H), 2.73 (ddd,
(
10) Representative Procedure and Spectroscopic Data –
Synthesis of Dimethyl 2-(3,4-Dihydro-1H-isochromen-1-
yl)malonate (3a)
1
3
In a sealable test tube equipped with a magnetic stir bar was
charged Cu(OTf) (9.5 mg, 0.026 mmol), InCl (5.8 mg,
J = 3.6, 3.6, 16.4 Hz, 1 H) ppm. C NMR (100 MHz,
CDCl ): d = 198.3, 137.8, 137.4, 134.3, 133.4, 129.3, 128.8,
2
3
3
0.026 mmol), and NHPI (17.1 mg, 0.105 mmol). The
128.6, 126.8, 126.5, 124.8, 73.0, 63.8, 45.9, 29.3 ppm. This
is a known compound and the spectral data are consistent
reaction vessel was sealed and flushed with O . The tube was
2
5
a
attached to a balloon of O and charged with dimethyl
with those reported in literature.
2
malonate (1a) (0.060 mL, 0.524 mmol) and isochroman (2a)
(12) Previously, we proposed a similar intermediate for the
oxidative arylation of cyclic benzyl amines with aryl boronic
(0.33 mL, 2.6 mmol). The test tube was placed in an oil bath
6
d
set at 55 °C and was allowed to stir overnight. The reaction
mixture was allowed to cooled to r.t. and the crude reaction
mixture was purified by silica gel column chromatography
acids.
(13) Although alcohol 6 was not observed during the
optimization process, we considered it to be a potential
intermediate since benzylic alcohols are known to undergo
alkylation with malonates and diketones in the presence of
metal salts. For recent examples, see: (a) Yasuda, M.;
Somyo, T.; Baba, A. Angew. Chem. Int. Ed. 2006, 45, 793.
(b) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett.
2007, 9, 825. (c) Kischel, J.; Mertins, K.; Michalik, D.;
Zapf, A.; Beller, M. Adv. Synth. Catal. 2007, 349, 865.
(d) Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Tetrahedron
Lett. 2007, 48, 3969. (e) Noji, M.; Konno, Y.; Ishii, K.
J. Org. Chem. 2007, 72, 5161.
(EtOAc–hexane, 1:4) to provide the desired alkylation
product 3a (107.1 mg, 0.405 mmol, 77%) as a clear colorless
oil.
1
H NMR (400 MHz, CDCl ): d = 7.18–7.08 (m, 3 H), 6.99
3
(
d, J = 7.6 Hz, 1 H), 5.45 (d, J = 6.0 Hz, 1 H), 4.15 (dddd,
J = 11.2, 4.8, 4.8, 1.6 Hz, 1 H), 3.98 (dd, J = 6.0, 2.0 Hz,
H), 3.80–3.73 (m, 1 H), 3.73 (d, J = 2.0 Hz, 3 H), 3.63 (d,
1
J = 2.0 Hz, 3 H), 3.01–2.94 (m, 1 H), 2.69 (d, J = 16.4 Hz,
1
1
5
H) ppm. 13C NMR (100 MHz, CDCl ): d = 168.2, 167.3,
3
34.8, 134.6, 129.3, 127.4, 126.5, 124.7, 74.3, 63.7, 58.2,
3.0, 52.7, 28.8 ppm. This is a known compound and the
(14) For the preparation of benzylic alcohol 6, see: Xu, Y. C.;
Lebeau, E.; Gillard, J. W.; Attardo, G. Tetrahedron Lett.
1993, 34, 3841.
spectral data are consistent with those reported in
literature.5b
(
11) Representative Procedure and Spectroscopic Data –
Synthesis of 2-(2,4-dihydro-1H-isochromen-1-yl)-1-
phenylethanone (5a)
(15) Metal salts are known to reductively decompose alkyl
hydroperoxides to its corresponding alkyloxy radical.
Conversely, metal salts can be oxidized by hydroperoxides
7
In a sealable test tube equipped with a magnetic stir bar was
charged Cu(OTf) (9.0 mg, 0.025 mmol), InCl (5.5 mg,
and generate hydroperoxide radicals.
(16) Jones, C. W. Application of Hydrogen Peroxide and
Derivatives, The Royal Society of Chemistry: Cambridge,
1999.
2
3
0.025 mmol), and NHPI (16.3 mg, 0.100 mmol). The
reaction vessel was sealed and flushed with O . The tube was
2
attached to a balloon of O and charged with acetophenone
2
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